Chronic Hypoxemia Research Articles

Myocardial Fistulisation and Coronary Arterial Ectasia in Children with Univentricular Circulation: An Under-Recognised Problem.

Among 241 children with univentricular circulation who underwent total cavopulmonary connection (Glenn or Fontan) over a 17years period (January 2000-April 2017), we found two patients who had diffuse coronary fistulisation of their myocardium (0.8%). We also report an additional third case from Oak Lawn, Illinois, USA. One of the children had documented normal coronary arteries and myocardium at catheterisation prior to development of the fistulisation process. The same child also developed extensive veno-venous collaterals. All children had evidence of elevated pulmonary arterial pressures and were treated with a combination of pulmonary vasodilators. The presence of chronic hypoxaemia and elevated filling pressures could potentially have contributed to coronary endothelial dysfunction, thereby giving rise to the coronary vasculopathy and myocardial fistulisation. Alternatively, this myocardial fistulisation process may be present from early in life and not recognised. This may necessitate early referral for orthotopic cardiac transplantation. Diffuse fistulisation of the myocardium in children and young adults with univentricular circulation may be an under-recognised occurrence and coronary angiography should be considered in these patients.

Palliative oxygen for chronic breathlessness: what new evidence?

Supplemental oxygen improves survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxaemia, but the effect of oxygen therapy in mild or moderate hypoxaemia to reduce symptomatic chronic breathlessness remains unclear. This review provides an overview of recent evidence about the role of oxygen therapy for the relief of chronic breathlessness in advanced illness. In COPD, a recent Cochrane review strengthens earlier findings regarding the positive effect of supplemental oxygen compared with air during exercise test in the training setting. The novel analysis of effect of oxygen therapy on quality of life (QoL) showed no clear effect. Short-burst oxygen therapy given before exercise had no effect and should not be used. Supplemental oxygen during exercise has been shown to reduce breathlessness in patients with COPD who have no or mild hypoxaemia, but it is not clear whether the reduction in breathlessness shown in the laboratory setting translates into a clinically important benefit. Further studies are needed to establish this.

Cerebral Oxygen Saturation in Children With Congenital Heart Disease and Chronic Hypoxemia.

Increased hemoglobin (Hb) concentration accompanying hypoxemia is a compensatory response to maintain tissue oxygen delivery. Near infrared spectroscopy (NIRS) is used clinically to detect abnormalities in the balance of cerebral tissue oxygen delivery and consumption, including in children with congenital heart disease (CHD). Although NIRS-measured cerebral tissue O2 saturation (ScO2) correlates with arterial oxygen saturation (SaO2), jugular bulb O2 saturation (SjbO2), and Hb, little data exist on the interplay between these factors and cerebral O2 extraction (COE). This study investigated the associations of ScO2 and ΔSaO2-ScO2 with SaO2 and Hb and verified the normal range of ScO2 in children with CHD. Children undergoing cardiac catheterization for CHD were enrolled in a calibration and validation study of the FORE-SIGHT NIRS monitor. Two pairs of simultaneous arterial and jugular bulb samples were drawn for co-oximetry, calculation of a reference ScO2 (REF CX), and estimation of COE. Pearson correlation and linear regression were used to determine relationships between O2 saturation parameters and Hb. Data were also analyzed according to diagnostic group defined as acyanotic (SaO2 ≥ 90%) and cyanotic (SaO2 < 90%). Of 65 children studied, acceptable jugular bulb samples (SjbO2 absolute difference between samples ≤10%) were obtained in 57 (88%). The ΔSaO2-SjbO2, ΔSaO2-ScO2, and ΔSaO2-REF CX were positively correlated with SaO2 and negatively correlated with Hb (all P < .001). Although by diagnostic group ScO2 differed statistically (P = .002), values in the cyanotic patients were within the range considered normal (69% ± 6%). COE estimated by the difference between arterial and jugular bulb O2 content (ΔCaO2-CjbO2, mL O2/100 mL) was not different for cyanotic and acyanotic patients (P = .10), but estimates using ΔSaO2-SjbO2, ΔSaO2-ScO2, or ΔSaO2-ScO2/SaO2 were significantly different between the cyanotic and acyanotic children (P < .001). Children with adequately compensated chronic hypoxemia appear to have ScO2 values within the normal range. The ΔSaO2-ScO2 is inversely related to Hb, with the implication that in the presence of reduced Hb, particularly if coupled with a decreased cardiac output, the ScO2 can fall to values associated with brain injury in laboratory studies.

The multi-level impact of chronic intermittent hypoxia on central auditory processing

During hypoxia, the tissues do not obtain adequate oxygen. Chronic hypoxia can lead to many health problems. A relatively common cause of chronic hypoxia is sleep apnea. Sleep apnea is a sleep breathing disorder that affects 3–7% of the population. During sleep, the patient's breathing starts and stops. This can lead to hypertension, attention deficits, and hearing disorders. In this study, we apply an established chronic intermittent hypoxemia (CIH) model of sleep apnea to study its impact on auditory processing. Adult rats were reared for seven days during sleeping hours in a gas chamber with oxygen level cycled between 10% and 21% (normal atmosphere) every 90s. During awake hours, the subjects were housed in standard conditions with normal atmosphere. CIH treatment significantly reduces arterial oxygen partial pressure and oxygen saturation during sleeping hours (relative to controls). After treatment, subjects underwent functional magnetic resonance imaging (fMRI) with broadband sound stimulation. Responses are observed in major auditory centers in all subjects, including the auditory cortex (AC) and auditory midbrain. fMRI signals from the AC are statistically significantly increased after CIH by 0.13% in the contralateral hemisphere and 0.10% in the ipsilateral hemisphere. In contrast, signals from the lateral lemniscus of the midbrain are significantly reduced by 0.39%. Signals from the neighboring inferior colliculus of the midbrain are relatively unaffected. Chronic hypoxia affects multiple levels of the auditory system and these changes are likely related to hearing disorders associated with sleep apnea.

Regulation of erythropoiesis after normoxic return from chronic sustained and intermittent hypoxia.

Hypoxia increases erythropoiesis mediated by hypoxia-inducible transcription factors (HIF), which regulate erythropoietin transcription. Neocytolysis is a physiological mechanism that corrects polycythemia from chronic sustained hypoxemia by transient, preferential destruction of young RBCs after normoxia is restored. We showed that neocytolysis is caused by excessive mitochondrial-derived reactive oxygen species in reticulocytes mediated by downregulation of HIF-controlled BNIP3L regulated mitophagy and a decrease in RBC antioxidant catalase (CAT) in hypoxia-produced erythrocytes. Decreased CAT results from hypoxia-induced miR-21 that downregulates CAT. This correlates with a transient acute decrease of HIF-1 at normoxic return that is associated with normalization of red cell mass.

Maternal chronic hypoxia increases expression of genes regulating lung liquid movement and surfactant maturation in male fetuses in late gestation.

Chronic fetal hypoxaemia is a common pregnancy complication associated with intrauterine growth restriction that may influence respiratory outcome at birth. We investigated the effect of maternal chronic hypoxia for a month in late gestation on signalling pathways regulating fetal lung maturation and the transition to air-breathing at birth using isobaric hypoxic chambers without alterations to maternal food intake. Maternal chronic hypoxia in late gestation increases fetal lung expression of genes regulating hypoxia signalling, lung liquid reabsorption and surfactant maturation, which may be an adaptive response in preparation for the successful transition to air-breathing at birth. In contrast to other models of chronic fetal hypoxaemia, late gestation onset fetal hypoxaemia promotes molecular regulation of fetal lung maturation. This suggests a differential effect of timing and duration of fetal chronic hypoxaemia on fetal lung maturation, which supports the heterogeneity observed in respiratory outcomes in newborns following exposure to chronic hypoxaemia in utero. Chronic fetal hypoxaemia is a common pregnancy complication that may arise from maternal, placental and/or fetal factors. Respiratory outcome of the infant at birth likely depends on the duration, timing and severity of the hypoxaemic insult. We have isolated the effect of maternal chronic hypoxia (MCH) for a month in late gestation on fetal lung development. Pregnant ewes were exposed to normoxia (21% O2 ) or hypoxia (10% O2 ) from 105 to 138days of gestation (term ∼145days). At 138days, gene expression in fetal lung tissue was determined by quantitative RT-PCR. Cortisol concentrations were determined in fetal plasma and lung tissue. Numerical density of surfactant protein positive cells was determined by immunohistochemistry. MCH reduced maternal PaO2 (106±2.9vs. 47±2.8mmHg) and fetal body weight (4.0±0.4vs. 3.2±0.9kg). MCH increased fetal lung expression of the anti-oxidant marker CAT and decreased expression of the pro-oxidant marker NOX-4. MCH increased expression of genes regulating hypoxia signalling and feedback (HIF-3α, KDM3A, SLC2A1, EGLN-3). There was no effect of MCH on fetal plasma/lung tissue cortisol concentrations, nor genes regulating glucocorticoid signalling (HSD11B-1, HSD11B-2, NR3C1, NR3C2). MCH increased expression of genes regulating sodium (SCNN1-B, ATP1-A1, ATP1-B1) and water (AQP-4) movement in the fetal lung. MCH promoted surfactant maturation (SFTP-B, SFTP-D, ABCA3) at the molecular level, but did not alter the numerical density of surfactant positive cells in lung tissue. MCH in late gestation promotes molecular maturation of the fetal lung, which may be an adaptive response in preparation for the successful transition to air-breathing at birth.

P209 Effect of normobaric hypoxia on pulmonary hemodynamics in patients with precapillary pulmonary hypertension

Introduction: Patients with precapillary pulmonary hypertension (PH, pulmonary arterial or chronic thromboembolic pulmonary hypertension, PAH/CTEPH) may experience disease deterioration upon exposure to a hypoxic environment during air travel or altitude sojourns due to hypoxic pulmonary vasoconstriction. We investigated the effect of breathing a hypoxic air mixture on pulmonary hemodynamics and blood gases in PH in comparison with unaffected controls. Methods: Patients scheduled for diagnostic right heart catheterization had hemodynamic assessments under ambient air (FiO2 0.21) and after 10 min of breathing nitrogen-enriched air (hypoxia FiO2 0.16). Patients were stratified according to their mean pulmonary arterial pressure (mPAP): PH (mPAP ≥25mmHg, pulmonary artery wedge pressure (PAWP) ≤15mmHg), unaffected controls (patients undergoing RHC for evaluation of dyspnea with mPAP< 20mmHg) and intermediate (mPAP 20-24mmHg). Results: 20 patients with PH (12 females, 8 PAH, 12 CTEPH; mean±SD age 63±14y), 12 controls (12 females, age 63±7y) and 7 patients from the intermediate group (3 females, age 66±12y) were included. PaO2 significantly decreased in all groups upon exposure to hypoxia (see table). However, hypoxemia was not accompanied by significant changes in mPAP or cardiac index in any group. Unexpectedly, pulmonary vascular resistance significantly increased in the control group. The test was well tolerated by all participants.TablePAH/CTEPH (n=20)Intermediate (n=7)Controls (n=12)FiO2 0.21Mean Change 95%CI with FiO2 0.16FiO2 0.21Mean Change 95%CI with FiO2 0.16FiO2 0.21Mean Change 95%CI with FiO2 0.16Heart Rate, bpm70±94 (1 to 7)*78±123 (0 to 6)68±95 (2 to 9)*mPAP, mmHg40.5±12.22.6 (-0.1 to 5.2)23.9±4.20.7 (-3.5 to 4.9)16.7±1.71.7 (-0.2 to 3.6)Cardiac index, l/min/m22.6±0.7-0.04 (-0.3 to 0.2)5.2±1.90.04 (-0.5 to 0.6)3.2±0.9-0.1 (-0.4 to 0.1)PVR index, WU6.1±3.30.7 (-0.2 to 1.7)1.3±0.40.04 (-0.5 to 0.6)1.8±0.70.6 (0.1 to 1.0)*SaO2(%)93.9±3.5-7.4 (-12.2 to -2.6)**95.7±2.8-4.4 (-10.0 to 1.1)97.3±1.5-4.9 (-7.8 to -2.0)**PaO2 (kPA)9.3±1.6-2.5 (-3.4 to -1.6)***10.4±1.7-2.7 (-5.2 to -0.3)*10.7±1.4-3.3 (-4.5 to -2.1)***PaCO2 (kPA)4.6±0.5-0.3 (-0.5 to -0.1)*4.8±1.9-0.6 (-1.4 to 0.1)4.4±1.0-0.2 (-0.7 to 0.3)Abbreviations: mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; SaO2: arterial oxygen saturation; PaO2: partial pressure of oxygen; PaCO2: partial pressure of carbon dioxide. Note: Data are given as mean±SD. Within group differences *: p<0.05; **: p<0.01; ***: p<0.001. Between group differences in the changes upon exposure to hypoxia were not statistically significant. Open table in a new tab Abbreviations: mPAP: mean pulmonary artery pressure; PVR: pulmonary vascular resistance; SaO2: arterial oxygen saturation; PaO2: partial pressure of oxygen; PaCO2: partial pressure of carbon dioxide. Note: Data are given as mean±SD. Within group differences *: p<0.05; **: p<0.01; ***: p<0.001. Between group differences in the changes upon exposure to hypoxia were not statistically significant. Conclusions: Our data suggest that a short-term exposure to a moderately reduced FiO2 in patients with PAH/CTEPH associated with chronic hypoxemia in sea level conditions seems not to further exacerbate derangements in pulmonary hemodynamics. Whether the hemodynamic effects of a short hypoxic challenge are in concordance with the response to prolonged hypoxia remains to be determined.

Effects of preoperative chronic hypoxemia on geriatrics outcomes after hip arthroplasty: A hospital-based retrospective analysis study.

The partial pressure of oxygen decreases as altitude increases, the preoperative chronic hypoxemia (CH) may have a plausible clinical impact. Risk factors for postoperative serious adverse events (pSAEs) in patients living in high altitudes during primary hip arthroplasty (HA) are not clear.This is an observational study embracing patients from January 1, 2011 to December 31, 2015 at Yan’an Hospital of Kunming City, a 1338-bed municipal teaching hospital of Kunming Medical University. Univariate analysis revealed that significant differences between patients with and without preoperative CH occurred in intraoperative hypotension (77 [33%] vs 34 [47%], P = .040) and that significant differences between patients with and without pSAEs occurred in following variables: preoperative CH (32 [57%] vs 199 [80%], P < .001), intraoperative hypotension (37 [66%] vs 74 [30%], P < .001), highest noradrenaline support (.09 [.01–.21] vs .03 [.01–.05] μg/kg/min, P < .001), higher application of general anesthesia (15 [27%] vs 29 [12%], P = .004), and lower of combined-spinal epidural anesthesia (CSEA) (21 [37%] vs 165 [66%], P < .001). The general anesthesia and intraoperative hypotension remained the independent risk factors for pSAEs (P < .05), while the preoperative CH presented by decreasing its risk (P < .05).This study suggests that various intraoperative events including general anesthesia, hypotension were risk factors for the development of pSAEs. Preoperative CH, presenting with decreased incidence of intensive care unit (ICU) admission and pSAEs, may mimic hypoxic preconditioning in organic protection, for which further study is needed to uncover the underlying mechanisms.

Efficacy of nasal cavity ventilation expansion surgery for OSAHS with multiplane obstruction

Objective:To evaluate the improvement of nasal obstruction sympotom， AHI and LSaO²of OSAHS patients with multiplane obstruction after nasal cavity ventilation expansion techniques.Method:All the 41 OSAHS patients diagnosed by PSG were assessed with multiplane obstruction after examinations.Nasal cavity ventilation expansion techniques were performed. Each patient received the examinations of acoustic rhinometry and nasal resistance to assess the objective nasal ventilation, completed the nasal obstruction symptom evaluation(NOSE) scale to assess the subjective nasal obstructon. Postoperative datas were obtained at least 3 months later. Result:①The unilateral nasal volume 0-5 cm（UV5）were significantly changed(P<0.05), whereas the nasal resistance(NR)and NOSE were significantly decreased(P<0.05);②the AHI was significantly decreased,the LSaO2 was significantly increased(P<0.05). Conclusion:①The nasal cavity ventilation expansion techniques can improve the nasal ventilation of OSAHS patients with multiplane obstruction;②the postoperative AHI was significantly decreased whereas the chronic hypoxemia of patients was improve after surgery. Nasal cavity ventilation expansion surgery was effective and helpful for the later treatments for OSAHS patients with multiplane obstruction.

Integrating postural and vestibular dimensions to depict impairment in moderate-to-severe obstructive sleep apnea syndrome patients.

Vestibular dysfunction was linked to moderate-to-severe obstructive sleep apnea syndrome (OSAS) patients in literature. However, due to a lack of knowledge among valid and recent implementations conceived to study postural control on static posturography (SP) and vestibulo-ocular reflex (VOR) gain under physiological conditions (video Head Impulse Test; vHIT), the aim of this work was to integrate (i) VOR changes via vHIT implementation, (ii) postural arrangement by studying both classical parameters and frequency spectra (PS) and (iii) correlation between these findings, polygraphic (PG) and subjective scores along Dizziness Handicap Inventory (DHI) and Epworth Sleepiness Scale (ESS). Thus, 32 moderate-to-severe OSAS patients and 32 healthy subjects - studied by using PG, DHI and ESS - underwent vHIT and SP posturographic assessment. Analysis of variance was performed to disclose between-group effects and correlation analysis was implemented between otoneurological, PG, DHI and ESS values. OSAS group demonstrated a significant decay of VOR gain and an increase in both frequency spectra PS values, especially within the low-frequency interval, and in classical posturographic SP parameters. Further, positive and negative correlations between mean SaO2 and gain and low frequency interval spectra PS were found, respectively. Strengthening previous hypothesis related to brainstem chronic hypoxemia phenomena affecting vestibular network, implementation of these data could generate future attentions (i) for screening under physiological conditions postural and vestibular detriments in OSAS subjects, especially exposed at risk settings, and (ii) among PG parameters, such as mean SaO2 , to propose further reliable tools in monitoring postural and vestibular decay in these patients demonstrating PG parameters detriments.

Are Permanent Residents of High Altitude Fully Adapted to Their Hypoxic Environment?

West, John B. Are permanent residents of high altitude fully adapted to their hypoxic environment? High Alt Med Biol. 18:135-139, 2017.-Millions of people live permanently at high altitude and many have been there for generations. It is sometimes claimed that these people have completely adapted to their environment, and certainly some remarkable genetic adaptations have recently been described. However there is now strong evidence that permanent residents are not completely adapted to the high altitude in the sense that they have fully compensated for the environmental hypoxia. By sea level standards, highlanders have severe chronic arterial hypoxemia. Furthermore, their maximum oxygen uptake increases if they descend, and recent measurements suggest that cognitive function is reduced in this population compared with a matched group at a lower altitude. Reproductive success is reduced at high altitude because neonatal mortality increases with altitude. The topic has recently gained importance because new technology enables the physiological altitude of permanent residents to be reduced by adding oxygen to the air of buildings on a large scale, a procedure known as oxygen conditioning. Its feasibility has been questioned, but in essence it is no different from air conditioning that is universally used to improve the well-being and productivity of millions of people in hot climates. Oxygen conditioning has the potential to do the same for permanent residents of high altitude.

Application of the National Early Warning Score (NEWS) as a stratification tool on admission in an Italian acute medical ward: A perspective study

We aimed to assess the performance of the National Early Warning Score (NEWS) as tool for patient risk stratification at admission in an acute Internal Medicine ward and to ensure patient placement in ward areas with the required and most appropriate intensity of care. As secondary objective, we considered NEWS performance in two subgroups of patients: sudden cardiac events (acute coronary syndromes and arrhythmic events), and chronic respiratory insufficiency. We conducted a perspective cohort single centre study on 2,677 unselected patients consecutively admitted from July 2013 to March 2015 in the Internal Medicine ward of the hospital of Trento, Italy. The NEWS was mandatory collected on ward admission. We defined three risk categories for clinical deterioration: low score (NEWS 0-4), medium score (NEWS 5-6), and high score (NEWS≥7). Following adverse outcomes were considered: total and early (<72hours) in-hospital mortality, urgent transfers to a higher intensity of care. A logistic regression model quantified the association between outcomes and NEWS. For patients with NEWS >4 vs patients with NEWS <4, the risk of early death increased from 12 to 36 times, total mortality from 3.5 to 9, and urgent transfers from 3.5 to 7. In patients with sudden cardiac events, lower scores were significantly associated with higher risk of transfer to a higher intensity of care. In patients affected by chronic hypoxaemia, adverse outcomes occurred less in medium and high score categories of NEWS. National Early Warning Score assessed on ward admission may enable risk stratification of clinical deterioration and can be a good predictor of in-hospital serious adverse outcomes, although sudden cardiac events and chronic hypoxaemia could constitute some limits.

Eisenmenger syndrome: current perspectives

Eisenmenger syndrome: current perspectives Heba Nashat,1–3 Aleksander Kempny,1–3 Colm McCabe,1 Laura C Price,1–3 Carl Harries,1 Rafael Alonso-Gonzalez,1–3 Michael A Gatzoulis,1–3 Stephen J Wort,1–3 Konstantinos Dimopoulos1–3 1Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, 2National Heart and Lung Institute (NHLI), Imperial College, 3National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, London, UK Abstract: Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). It results from a cardiac defect allowing significant systemic-to-pulmonary (left-to-right) shunting, which triggers the development of pulmonary vascular disease (PVD) if the defect is not repaired in a timely fashion. Once severe PVD has developed, the defect cannot be repaired. With advances in pediatric cardiology and surgery, the prevalence of ES is steadily falling in developed countries; nonetheless, there will always be patients who are unsuitable for repair at the time of diagnosis, or emigrating from countries with less advanced healthcare, who will develop ES. ES is a multisystem disorder causing chronic hypoxemia and reduced cardiac output resulting in significant morbidity and mortality. While lung (plus defect repair) or combined heart and lung transplantation is thought be the definitive treatment for ES, transplant organs are a limited resource and long-term results are still suboptimal. PAH pharmacotherapy was, until quite recently, largely directed at symptomatic relief and had no impact on morbidity and mortality. Targeted PAH therapies have recently been proven to be beneficial in various forms of PAH in terms of functional status, progression of disease, and prognosis. Data on the effect of PAH therapies in the ES cohort remain limited, but available studies demonstrate evidence of improvement in symptoms, exercise capacity, and some evidence of survival benefit. ES patients should be followed in specialized centers, by means of an interdisciplinary approach by clinicians experienced in PAH and CHD. However, local physicians working in cardiology, respiratory medicine, primary care, and emergency services are likely to encounter ES patients and need to be aware of the main issues and pitfalls in their care. The authors present an overview of the management of ES, focusing on the most common issues and complications. Keywords: Eisenmenger syndrome, pulmonary arterial hypertension, congenital heart disease, cyanosis, pulmonary arterial hypertension therapies, hyperviscosity, thrombosis, bleeding, pregnancy, Down syndrome

Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep.

Fetal insulin secretion is inhibited by acute hypoxemia. The relationship between prolonged hypoxemia and insulin secretion, however, is less well defined. To test the hypothesis that prolonged fetal hypoxemia impairs insulin secretion, studies were performed in sheep fetuses that were bled to anemic conditions for 9 ± 0 days (anemic, n = 19) and compared with control fetuses (n = 15). Arterial hematocrit and oxygen content were 34% and 52% lower, respectively, in anemic vs. control fetuses (P < 0.0001). Plasma glucose concentrations were 21% higher in the anemic group (P < 0.05). Plasma norepinephrine and cortisol concentrations increased 70% in the anemic group (P < 0.05). Glucose-, arginine-, and leucine-stimulated insulin secretion all were lower (P < 0.05) in anemic fetuses. No differences in pancreatic islet size or β-cell mass were found. In vitro, isolated islets from anemic fetuses secreted insulin in response to glucose and leucine as well as control fetal islets. These findings indicate a functional islet defect in anemic fetuses, which likely involves direct effects of low oxygen and/or increased norepinephrine on insulin release. In pregnancies complicated by chronic fetal hypoxemia, increasing fetal oxygen concentrations may improve insulin secretion.

Oxygen exchange and energy metabolism in erythrocytes of Rett syndrome and their relationships with respiratory alterations.

Rett syndrome (RTT) is a neurodevelopmental disorder, mainly affecting females, which is associated to a mutation on the methyl-CpG-binding protein 2 gene. In the pathogenesis and progression of classic RTT, red blood cell (RBC) morphology has been shown to be an important biosensor for redox imbalance and chronic hypoxemia. Here we have evaluated the impact of oxidation and redox imbalance on several functional properties of RTT erythrocytes. In particular, we report for the first time a stopped-flow measurement of the kinetics of oxygen release by RBCs and the analysis of the intrinsic affinity of the hemoglobin (Hb). According to our experimental approach, RBCs from RTT patients do not show any intrinsic difference with respect to those from healthy controls neither in Hb's oxygen-binding affinity nor in O2 exchange processes at 37°C. Therefore, these factors do not contribute to the observed alteration of the respiratory function in RTT patients. Moreover, the energy metabolism of RBCs, from both RTT patients and controls, was evaluated by ion-pairing HPLC method and related to the level of malondialdehyde and to the oxidative radical scavenging capacity of red cells. Results have clearly confirmed significant alterations in antioxidant defense capability, adding important informations concerning the high-energy compound levels in RBCs of RTT subjects, underlying possible correlations with inflammatory tissue alterations.

The Association between Chronic Obstructive Pulmonary Disease (COPD) and Atrial Fibrillation: A Review

COPD is one of the leading causes of Mortality & Morbidity in the US and is associated with a wide variety of cardiovascular diseases especially arrhythmias, angina, myocardial infarction and congestive heart failure and is directly associated with the severity of COPD described in the GOLD initiative. COPD is an independent risk factor for AF/AFL. Smoking, hypoxia and inflammation all contribute to AF in COPD patients mainly via atrial remodeling while hypercapnia contributes to it via increasing refractoriness of the atrial musculature and a delay in the return of the refractoriness to normal after resolution of the hypercapnia. The most common EKG abnormality found in patients with COPD is P pulmonale and the PQ interval is the strongest predictor of developing AF. The P wave Dispersion (PwD) was also an independent risk factor for the development of AF and was found to be more in the acute phase than in the stable phase. The BODE index, an important prognostic score among patients hospitalized with a COPD exacerbation has a direct co relation with the prevalence of AF/AFL while the DECAF score, which was found to be superior to the CURB 65 score as a mortality predictor for hospitalized patients, includes AF as one of the criteria. Chronic hypoxemia is one of the main reasons for altered pulmonary vein anatomy and hence the presence of COPD was identified as an independent risk factor for the recurrence of atrial tachyarrhythmias after catheter ablation in patients with COPD and the absence of COPD was also found to be an independent predictor for a successful electro-cardioversion. These patients were also found to have an increased incidence of non-PV foci for the arrhythmias. Oral glucocorticoids were associated with an increased risk of developing AF especially high dose steroids. It is recommended to correct the underlying respiratory decompensation while treating patients with AF as they render the treatment of AF ineffective. Non-dihydropyridine calcium channel blockers should be used as first line rate control agents for AF in patients with concomitant COPD while the β-blockers, sotalol, propafenone can be used in patients with obstructive lung disease who do not have bronchospasm.

Влияние хронической гипоксемии и высокой концентрации гемоглобина на развитие осложнений в раннем послеоперационном периоде у больных с врожденными пороками сердца цианотического типа после операций с искусственным кровообращением

&lt;b&gt;Цель исследования&lt;/b&gt; – определить, является ли хроническая гипоксемия или высокая концентрация гемоглобина перед началом оперативного вмешательства предиктором развития осложнений у больных с врожденными пороками сердца, и оценить их влияние на динамику показателей сывороточного лактата и системы гемостаза в раннем послеоперационном периоде. &lt;br /&gt; &lt;b&gt;Материал и методы.&lt;/b&gt; В исследование включены 93 больных, проведен сравнительный анализ двух групп – с осложненным и неосложненным течением раннего послеоперационного периода. Для исследования влияния хронической гипоксемии и концентрации гемоглобина на развитие ранних послеоперационных осложнений использовался ROC-анализ. Определяли наличие корреляционной связи между парциальным давлением кислорода артериальной крови и концентрацией сывороточного лактата, показателями гемостаза. А также связь этих показателей с концентрацией гемоглобина до операции. &lt;br /&gt; &lt;b&gt;Результаты.&lt;/b&gt; Между группами с осложнениями и без осложнений обнаружены статистически достоверные отличия по величине исходной гипоксемии, уровню сывороточного лактата и значениям МНО при поступлении в ОРИТ. Отличия по концентрации гемоглобина отсутствовали. При анализе зависимости развития органных дисфункций в раннем послеоперационном периоде от значений парциального давления кислорода артериальной крови до операции было выявлено, что гипоксемия может служить предиктором развития осложнений (AUC=0,687, порог отсечения 203 мм рт. ст.). Исследование взаимосвязи развития осложнений и концентрации гемоглобина показало неудовлетворительное качество модели. Статистически достоверная корреляция парциального давления кислорода артериальной крови обнаружена с показателями гемостаза. Концентрация гемоглобина связана с максимальной концентрацией сывороточного лактата в 1-е сутки после операции, а также с показателями гемостаза. &lt;br /&gt; &lt;b&gt;Заключение.&lt;/b&gt; Ведущую роль в развитии ранних послеоперационных осложнений играет хроническая гипоксемия. Исходная гипоксемия связана с коагулопатией, но не концентрацией сывороточного лактата. Высокий уровень гемоглобина у больных с цианозом ассоциирован с ростом уровня сывороточного лактата и коагулопатией, но не с риском ранних послеоперационных осложнений. HTML

Uncoupling protein 2 downregulation by hypoxia through repression of peroxisome proliferator-activated receptor γ promotes chemoresistance of non-small cell lung cancer.

Hypoxic microenvironment is critically involved in the response of non-small cell lung cancer (NSCLC) to chemotherapy, the mechanisms of which remain largely unknown. Here, we found that NSCLC patients exhibited increased chemotherapeutic resistance when complicated by chronic obstructive pulmonary disease (COPD), a critical cause of chronic hypoxemia. The downregulation of uncoupling protein 2 (UCP2), which is attributed to hypoxia-inducible factor 1 (HIF-1)-mediated suppression of the transcriptional factor peroxisome proliferator-activated receptor γ (PPARγ), was involved in NSCLC chemoresistance, and predicted a poor survival rate of patients receiving routine chemotherapy. UCP2 suppression induced reactive oxygen species production and upregulation of the ABC transporter protein ABCG2, which leads to chemoresistance by promoting drug efflux. UCP2 downregulation also altered metabolic rates as shown by elevated glucose uptake and reduced oxygen consumption. These data suggest that UCP2 is a key mediator of hypoxia-triggered chemoresistance of NSCLCs, which can be potentially targeted in clinical treatment of chemo-refractory NSCLCs.

Early restriction of placental growth results in placental structural and gene expression changes in late gestation independent of fetal hypoxemia.

Placental restriction and insufficiency are associated with altered patterns of placental growth, morphology, substrate transport capacity, growth factor expression, and glucocorticoid exposure. We have used a pregnant sheep model in which the intrauterine environment has been perturbed by uterine carunclectomy (Cx). This procedure results in early restriction of placental growth and either the development of chronic fetal hypoxemia (PaO2≤17 mmHg) in late gestation or in compensatory placental growth and the maintenance of fetal normoxemia (PaO2>17 mmHg). Based on fetal PaO2, Cx, and Control ewes were assigned to either a normoxemic fetal group (Nx) or a hypoxemic fetal group (Hx) in late gestation, resulting in 4 groups. Cx resulted in a decrease in the volumes of fetal and maternal connective tissues in the placenta and increased placental mRNA expression of IGF2, vascular endothelial growth factor (VEGF), VEGFR‐2,ANGPT2, and TIE2. There were reduced volumes of trophoblast, maternal epithelium, and maternal connective tissues in the placenta and a decrease in placental GLUT1 and 11βHSD2 mRNA expression in the Hx compared to Nx groups. Our data show that early restriction of placental growth has effects on morphological and functional characteristics of the placenta in late gestation, independent of whether the fetus becomes hypoxemic. Similarly, there is a distinct set of placental changes that are only present in fetuses that were hypoxemic in late gestation, independent of whether Cx occurred. Thus, we provide further understanding of the different placental cellular and molecular mechanisms that are present in early placental restriction and in the emergence of later placental insufficiency.

Oxygen for breathlessness in patients with chronic obstructive pulmonary disease who do not qualify for home oxygen therapy.

Breathlessness is a cardinal symptom of chronic obstructive pulmonary disease (COPD). Long-term oxygen therapy (LTOT) is given to improve survival time in people with COPD and severe chronic hypoxaemia at rest. The efficacy of oxygen therapy for breathlessness and health-related quality of life (HRQOL) in people with COPD and mild or no hypoxaemia who do not meet the criteria for LTOT has not been established. To determine the efficacy of oxygen versus air in mildly hypoxaemic or non-hypoxaemic patients with COPD in terms of (1) breathlessness; (2) HRQOL; (3) patient preference whether to continue therapy; and (4) oxygen-related adverse events. We searched the Cochrane Airways Group Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase, to 12 July 2016, for randomised controlled trials (RCTs). We handsearched the reference lists of included articles. We included RCTs of the effects of non-invasive oxygen versus air on breathlessness, HRQOL or patient preference to continue therapy among people with COPD and mild or no hypoxaemia (partial pressure of oxygen (PaO2) > 7.3 kPa) who were not already receiving LTOT. Two review authors independently assessed articles for inclusion in the review. Two review authors independently collected and analysed data. We assessed risk of bias by using the Cochrane 'Risk of bias tool'. We pooled effects recorded on different scales as standardised mean differences (SMDs) with 95% confidence intervals (CIs) using random-effects models. Lower SMDs indicated decreased breathlessness and reduced HRQOL. We performed subanalyses and sensitivity analyses and assessed the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. Compared with the previous review, which was published in 2011, we included 14 additional studies (493 participants), excluded one study and included data for meta-analysis of HRQOL. In total, we included in this review 44 studies including 1195 participants, and we included 33 of these (901 participants)in the meta-analysis.We found that breathlessness during exercise or daily activities was reduced by oxygen compared with air (32 studies; 865 participants; SMD -0.34, 95% CI -0.48 to -0.21; I2 = 37%; low-quality evidence). This translates to a decrease in breathlessness of about 0.7 points on a 0 to 10 numerical rating scale. In contrast, we found no effect of short-burst oxygen given before exercise (four studies; 90 participants; SMD 0.01, 95% CI -0.26 to 0.28; I2 = 0%; low-quality evidence). Oxygen reduced breathlessness measured during exercise tests (25 studies; 442 participants; SMD -0.34, 95% CI -0.46 to -0.22; I2 = 29%; moderate-quality evidence), whereas evidence of an effect on breathlessness measured in daily life was limited (two studies; 274 participants; SMD -0.13, 95% CI, -0.37 to 0.11; I2 = 0%; low-quality evidence).Oxygen did not clearly affect HRQOL (five studies; 267 participants; SMD 0.10, 95% CI -0.06 to 0.26; I2 = 0%; low-quality evidence). Patient preference and adverse events could not be analysed owing to insufficient data. We are moderately confident that oxygen can relieve breathlessness when given during exercise to mildly hypoxaemic and non-hypoxaemic people with chronic obstructive pulmonary disease who would not otherwise qualify for home oxygen therapy. Most evidence pertains to acute effects during exercise tests, and no evidence indicates that oxygen decreases breathlessness in the daily life setting. Findings show that oxygen does not affect health-related quality of life.